Research Triangle Park

About: Research Triangle Park is a nonprofit organization based out in Durham, North Carolina, United States. It is known for research contribution in the topics: Population & Environmental exposure. The organization has 24961 authors who have published 35800 publications receiving 1684504 citations. The organization is also known as: RTP.

Specific nonopiate receptors for beta-endorphin

Abstract: Iodinated beta H-[2-D-alanine]endorphin exhibits specific binding to cultured human lymphocytes The binding is inhibited by low concentrations of beta-endorphin and its D-alanine derivative, but is not affected by opiate agonists and antagonists, or by enkephalin analogs, beta-lipotropin, adrenocorticotrophic hormone, or alpha-melanocyte-stimulating hormone; this suggests the existence of a specific, non-opiate binding site (receptor) for beta-endorphin The carboxy-terminal region of beta-endorphin is essential for this binding activity, since alpha-endorphin is not active beta-Endorphin may be a circulating hormone with peripheral physiological effects that are not primarily mediated through interactions with opiate or enkephalin receptors

Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks' gestation between 1993 and 1998.

Abstract: Objective. This study evaluated the impact of changes in perinatal management on neurodevelopmental impairment (NDI) at 18 to 22 months’ corrected age of low gestation (22–26 weeks) and higher gestation (27–32 weeks) extremely low birth weight infants (401–1000 g birth weight) who were cared for in the National Institute of Child Health and Human Development Neonatal Research Network during 3 epochs (1993–1994, 1995–1996, and 1997–1998). It was hypothesized that outcomes would improve over the 3 epochs. Methods. A multicenter cohort study was conducted of the outcomes of 3785 infants with assessments at 18 to 22 months’ corrected age. Regression analyses were completed to evaluate for epoch effects, gestational age effects, and time plus gestational age interaction. Regression analyses were also performed to identify the independent associations of epoch and 4 study perinatal interventions: antenatal steroids (yes, no), high-frequency ventilation (yes, no), number of days to regain birth weight as a marker of nutritional intake, and postnatal steroids for treatment of bronchopulmonary dysplasia (yes, no) with outcomes. Results. Survival improved for both the low (55%–61%) and higher (82%–86%) gestational age groups during the 3 epochs. Regression analyses indicated that the decreased risk for adverse outcome was significantly lower in epoch 2 compared with epoch 1 with decreased rates of low Bayley Mental Development Index (MDI) and neurodevelopmental impairment (NDI). Antenatal steroids were associated with decreased risk for moderate to severe cerebral palsy (CP) and low Bayley Psychomotor Development Index. High-frequency ventilation was associated with a low Bayley MDI and NDI, and postnatal steroids were associated with moderate to severe CP, any CP, low Bayley MDI, low Bayley Psychomotor Development Index, and increased NDI. Conclusion. Survival of extremely low birth weight infants improved between 1993 and 1998. Although some outcomes remained unchanged, the rates of low Bayley MDI scores and NDI improved. Antenatal steroid administration was the only study intervention associated with improved outcomes.

Nitrite as regulator of hypoxic signaling in mammalian physiology

Abstract: In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.

How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop.

Abstract: Workshop participants agreed that genotoxicity tests in mammalian cells in vitro produce a remarkably high and unacceptable occurrence of irrelevant positive results (e.g. when compared with rodent carcinogenicity). As reported in several recent reviews, the rate of irrelevant positives (i.e. low specificity) for some studies using in vitro methods (when compared to this "gold standard") means that an increased number of test articles are subjected to additional in vivo genotoxicity testing, in many cases before, e.g. the efficacy (in the case of pharmaceuticals) of the compound has been evaluated. If in vitro tests were more predictive for in vivo genotoxicity and carcinogenicity (i.e. fewer false positives) then there would be a significant reduction in the number of animals used. Beyond animal (or human) carcinogenicity as the "gold standard", it is acknowledged that genotoxicity tests provide much information about cellular behaviour, cell division processes and cellular fate to a (geno)toxic insult. Since the disease impact of these effects is seldom known, and a verification of relevant toxicity is normally also the subject of (sub)chronic animal studies, the prediction of in vivo relevant results from in vitro genotoxicity tests is also important for aspects that may not have a direct impact on carcinogenesis as the ultimate endpoint of concern. In order to address the high rate of in vitro false positive results, a 2-day workshop was held at the European Centre for the Validation of Alternative Methods (ECVAM), Ispra, Italy in April 2006. More than 20 genotoxicity experts from academia, government and industry were invited to review data from the currently available cell systems, to discuss whether there exist cells and test systems that have a reduced tendency to false positive results, to review potential modifications to existing protocols and cell systems that might result in improved specificity, and to review the performance of some new test systems that show promise of improved specificity without sacrificing sensitivity. It was concluded that better guidance on the likely mechanisms resulting in positive results that are not biologically relevant for human health, and how to obtain evidence for those mechanisms, is needed both for practitioners and regulatory reviewers. Participants discussed the fact that cell lines commonly used for genotoxicity testing have a number of deficiencies that may contribute to the high false positive rate. These include, amongst others, lack of normal metabolism leading to reliance on exogenous metabolic activation systems (e.g. Aroclor-induced rat S9), impaired p53 function and altered DNA repair capability. The high concentrations of test chemicals (i.e. 10 mM or 5000 microg/ml, unless precluded by solubility or excessive toxicity) and the high levels of cytotoxicity currently required in mammalian cell genotoxicity tests were discussed as further potential sources of false positive results. Even if the goal is to detect carcinogens with short in vitro tests under more or less acute conditions, it does not seem logical to exceed the capabilities of cellular metabolic turnover, activation and defence processes. The concept of "promiscuous activation" was discussed. For numerous mutagens, the decisive in vivo enzymes are missing in vitro. However, if the substrate concentration is increased sufficiently, some other enzymes (that are unimportant in vivo) may take over the activation-leading to the same or a different active metabolite. Since we often do not use the right enzyme systems for positive controls in vitro, we have to rely on their promiscuous activation, i.e. to use excessive concentrations to get an empirical correlation between genotoxicity and carcinogenicity. A thorough review of published and industry data is urgently needed to determine whether the currently required limit concentration of 10mM or 5000 microg/ml, and high levels of cytotoxicity, are necessary for the detection of in vivo genotoxins and DNA-reactive, mutagenic carcinogens. In addition, various measures of cytotoxicity are currently allowable under OECD test guidelines, but there are few comparative data on whether different measures would result in different maximum concentrations for testing. A detailed comparison of cytotoxicity assessment strategies is needed. An assessment of whether test endpoints can be selected that are not intrinsically associated with cytotoxicity, and therefore are less susceptible to artefacts produced by cytotoxicity, should also be undertaken. There was agreement amongst the workshop participants that cell systems which are p53 and DNA-repair proficient, and have defined Phase 1 and Phase 2 metabolism, covering a broad set of enzyme forms, and used within the context of appropriately set limits of concentration and cytotoxicity, offer the best hope for reduced false positives. Whilst there is some evidence that human lymphocytes are less susceptible to false positives than the current rodent cell lines, other cell systems based on HepG2, TK6 and MCL-5 cells, as well as 3D skin models based on primary human keratinocytes also show some promise. Other human cell lines such as HepaRG, and human stem cells (the target for carcinogenicity) have not been used for genotoxicity investigations and should be considered for evaluation. Genetic engineering is also a valuable tool to incorporate missing enzyme systems into target cells. A collaborative research programme is needed to identify, further develop and evaluate new cell systems with appropriate sensitivity but improved specificity. In order to review current data for selection of appropriate top concentrations, measures and levels of cytotoxicity, metabolism, and to be able to improve existing or validate new assay systems, the participants called for the establishment of an expert group to identify the in vivo genotoxins and DNA-reactive, mutagenic carcinogens that we expect our in vitro genotoxicity assays to detect as well as the non-genotoxins and non-carcinogens we expect them not to detect.